1. Field of the Invention
The present invention relates to a composition for safe and effective inhibition of pancreatic lipase and its use and a method for producing said composition.
2. Description of the Related Art
Digestion and absorption of dietary fat are regulated by the action of pancreatic triglyceride lipase (PTL), and colipase which is a small protein cofactor and is needed by pancreatic lipase for efficient dietary lipid hydrolysis. The enzyme and cofactor are excreted from the pancreas to duodenum. PTL is the primary lipase that hydrolyzes dietary fat molecules in the human duodenum and converts triglyceride substrates to monoglycerides and free fatty acids. The resulting monomers (2 free fatty acids and one 2-monoacylglycerol) are packed into micelle and then absorbed into the lymphatic system by a specialized vessel called a lacteal. Colipase, an enzyme belonging to family of pancreatic lipases, binds to the non-catalytic domain of lipase, and increases stability and hydrophobicity of the binding site. Colipase also prevents the inhibitory effect of various dietary factors on the lipase-catalyzed hydrolysis of dietary long-chain triglycerides.
Blocking the mechanisms of dietary fat digestion and absorption has been utilized in management of obesity. Inhibition of PTL activity with tetrahydrolipostatin (Orlistat/Xenical) and its diluted version, sold over-the-counter under the brand name of “Alli”, has been widely used in the pharmacotherapy of obesity. While tetrahydrolipostatin based products have been clinically proven as safe and effective, there are several known side effects and potential side effects of therapy.
The primary side effects of the drug are gastrointestinal tract-related, and include steatorrhea (oily, loose stools with excessive intestinal putrefaction and flatus due to unabsorbed fats reaching the large intestine), fecal incontinence, frequent bowel movements and urgent bowel movements. The potential organ toxicity of tetrahydrolipostatin has been signaled by the U.S. Food and Drug Administration (FDA). On May 26, 2010, the FDA has approved a revised label for tetrahydrolipostatin based drugs to include new safety information about cases of liver injury that have been reported rarely with the use of this medication (Non-Patent Document 1).
The use of tetrahydrolipostatin has been associated with isolated cases of acute kidney injury, possibly due to the fat malabsorption resulting from the excessive inhibition of pancreatic lipase, leading to the formation of soaps of fatty acid with calcium and resulting in increased free oxalate absorption and hyperoxaluria (Non-Patent Document 2).
Absorption of fat-soluble vitamins and other fat-soluble nutrients may be compromised with tetrahydrolipostatin, and thus, supplemental multivitamin containing vitamins A, D, E, K, and beta-carotene should be taken once a day while on tetrahydrolipostatin therapy to prevent the therapy associated vitamin deficiency.
There are also recognized shortfalls of the weight loss mechanism of tetrahydrolipostatin, including increasing appetite and time dependent diminishing drug efficacy occurring after several weeks of treatment. In one study, perception of satiety was significantly decreased in subjects on tetrahydrolipostatin coinciding with the significant decrease in circulating satiety hormones, i.e., CCK, PYY, and GLP-1 in the study subjects (Non-Patent Document 3).
As described above, current generation of pancreatic lipase inhibitors have potentially serious side effects and their efficacy tend to decrease with prolonged use, i.e., tachyphylaxis and increases levels of appetite may cause diminishing their weight loss potential.